Biodegradable drug delivery system

ABSTRACT

A drug delivery system (DDS) comprised of segmented biodegradable implants sized and suitable for implantation in an ocular region or site and methods for treating ocular conditions. The segmented implants provide an extended release of an active agent at a therapeutically effective amount for a period of time between 50 days and one year, or longer, and permit the DDS to have segments that possess individual and different drug release characteristics.

BACKGROUND

This invention relates to drug delivery systems (e.g. implants), as wellas to methods for treating ocular conditions with extended or sustaineddrug release. In particular the present invention relates to implantsand methods for treating an ocular condition by implanting into anocular region or site a drug delivery system comprising a plurality ofextended release bioerodible implant segment, each segment comprising anactive agent and a bioerodible polymer. The segmented bioerodibleimplants of this invention have varying and extended release rates toprovide for improved kinetics of release of one or more active(therapeutic) agents over time.

An ocular condition can include a disease, aliment or condition whichaffects or involves the eye or one of the parts or regions of the eye.Broadly speaking the eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball. An anterior ocular condition is adisease, ailment or condition which affects or which involves ananterior (i.e. front of the eye) ocular region or site, such as aperiocular muscle, an eye lid or an eye ball tissue or fluid which islocated anterior to the posterior wall of the lens capsule or ciliarymuscles. Thus, an anterior ocular condition primarily affects orinvolves, the conjunctiva, the cornea, the conjunctiva, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site. A posterior ocular condition is a disease,ailment or condition which primarily affects or involves a posteriorocular region or site such as choroid or sclera (in a position posteriorto a plane through the posterior wall of the lens capsule), vitreous,vitreous chamber, retina, optic nerve (i.e. the optic disc), and bloodvessels and nerves which vascularize or innervate a posterior ocularregion or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, macular degeneration (such asnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (such as cystoid macular edema anddiabetic macular edema); Behcet's disease, retinal disorders, diabeticretinopathy (including proliferative diabetic retinopathy); retinalarterial occlusive disease; central retinal vein occlusion; uveiticretinal disease; retinal detachment; ocular trauma which affects aposterior ocular site or location; a posterior ocular condition causedby or influenced by an ocular laser treatment; posterior ocularconditions caused by or influenced by a photodynamic therapy;photocoagulation; radiation retinopathy; epiretinal membrane disorders;branch retinal vein occlusion; anterior ischemic optic neuropathy;non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa andglaucoma. Glaucoma can be considered a posterior ocular conditionbecause the therapeutic goal is to prevent the loss of or reduce theoccurrence of loss of vision due to damage to or loss of retinal cellsor optic nerve cells (i.e. neuroprotection).

An anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

The present invention is concerned with and directed to a drug deliverysystem and methods for the treatment of an ocular condition, such as ananterior ocular condition or a posterior ocular condition or to anocular condition which can be characterized as both an anterior ocularcondition and a posterior ocular condition.

Therapeutic compounds useful for the treatment of an ocular conditioncan include active agents with, for example, an anti-neoplastic,anti-angiogenesis, kinase inhibition, anticholinergic, anti-adrenergicand/or anti-inflammatory activity.

Macular degeneration, such as age related macular degeneration (“AMD”)is the leading cause of blindness in the world. It is estimated thatthirteen million Americans have evidence of macular degeneration.Macular degeneration results in a break down the macula, thelight-sensitive part of the retina responsible for the sharp, directvision needed to read or drive. Central vision is especially affected.Macular degeneration is diagnosed as either dry (atrophic) or wet(exudative). The dry form of macular degeneration is more common thanthe wet form of macular degeneration, with about 90% of AMD patientsbeing diagnosed with dry AMD. The wet form of the disease usually leadsto more serious vision loss. Macular degeneration can produce a slow orsudden painless loss of vision. The cause of macular degeneration is notclear. The dry form of AMD may result from the aging and thinning ofmacular tissues, depositing of pigment in the macula, or a combinationof the two processes. With wet AMD, new blood vessels grow beneath theretina and leak blood and fluid. This leakage causes retinal cells todie and creates blind spots in central vision.

Macular edema (“ME”) can result in a swelling of the macula. The edemais caused by fluid leaking from retinal blood vessels. Blood leaks outof the weak vessel walls into a very small area of the macula which isrich in cones, the nerve endings that detect color and from whichdaytime vision depends. Blurring then occurs in the middle or just tothe side of the central visual field. Visual loss can progress over aperiod of months. Retinal blood vessel obstruction, eye inflammation,and age-related macular degeneration have all been associated withmacular edema. The macula may also be affected by swelling followingcataract extraction. Symptoms of ME include blurred central vision,distorted vision, vision tinted pink and light sensitivity. Causes of MEcan include retinal vein occlusion, macular degeneration, diabeticmacular leakage, eye inflammation, idiopathic central serouschorioretinopathy, anterior or posterior uveitis, pars planitis,retinitis pigmentosa, radiation retinopathy, posterior vitreousdetachment, epiretinal membrane formation, idiopathic juxtafovealretinal telangiectasia, Nd:YAG capsulotomy or iridotomy. Some patientswith ME may have a history of use of topical epinephrine orprostaglandin analogs for glaucoma. The first line of treatment for MEis typically anti-inflammatory drops topically applied.

An anti-inflammatory (i.e. immunosuppressive) agent can be used for thetreatment of an ocular condition, such as a posterior ocular condition,which involves inflammation, such as an uveitis or macula edema. Thus,topical or oral glucocorticoids have been used to treat uveitis. A majorproblem with topical and oral drug administration is the inability ofthe drug to achieve an adequate (i.e. therapeutic) intraocularconcentration. See e.g. Bloch-Michel E. (1992). Opening address:intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol, W. R. F.Böke et al. editors, Basel: Karger, 23:1-2; Pinar, V., et al. (1997).Intraocular inflammation and uveitis” In Basic and Clinical ScienceCourse. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Böke, W. (1992). Clinicalpicture of intermediate uveitis, In Intermediate Uveitis, Dev.Ophthalmol. W. R. F. Böke et al. editors, Basel: Karger, 23:20-7; andCheng C-K et al. (1995). Intravitreal sustained-release dexamethasonedevice in the treatment of experimental uveitis, Invest. Ophthalmol.Vis. Sci. 36:442-53.

Systemic glucocorticoid administration can be used alone or in additionto topical glucocorticoids for the treatment of uveitis. However,prolonged exposure to high plasma concentrations (administration of 1mg/kg/day for 2-3 weeks) of steroid is often necessary so thattherapeutic levels can be achieved in the eye.

Unfortunately, these high drug plasma levels commonly lead to systemicside effects such as hypertension, hyperglycemia, increasedsusceptibility to infection, peptic ulcers, psychosis, and othercomplications. Cheng C-K et al. (1995). Intravitreal sustained-releasedexamethasone device in the treatment of experimental uveitis, Invest.Ophthalmol. Vis. Sci. 36:442- 53 ; Schwartz, B. (1966). The response ofocular pressure to corticosteroids, Ophthalmol. Clin. North Am.6:929-89; Skalka, H. W. et al. (1980). Effect of corticosteroids oncataract formation, Arch Ophthalmol 98:1773-7; and Renfro, L. et al.(1992). Ocular effects of topical and systemic steroids, DermatologicClinics 10:505-12.

Additionally, delivery to the eye of a therapeutic amount of an activeagent can be difficult, if not impossible, for drugs with short plasmahalf-lives since the exposure of the drug to intraocular tissues islimited. Therefore, a more efficient way of delivering a drug to treat aposterior ocular condition is to place the drug directly in the eye,such as directly into the vitreous. Maurice, D. M. (1983).Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee,V. H. L. et al. (1989). “Drug delivery to the posterior segment” Chapter25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby,Vol. 1, pp. 483-98; and Olsen, T. W. et al. (1995). Human scleralpermeability: effects of age, cryotherapy, transscleral diode laser, andsurgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.

Techniques such as intravitreal injection of a drug have shown promisingresults, but due to the short intraocular half-life of active agent,such as glucocorticoids (approximately 3 hours), intravitreal injectionsmust be frequently repeated to maintain a therapeutic drug level. Inturn, this repetitive process increases the potential for side effectssuch as retinal detachment, endophthalmitis, and cataracts. Maurice, D.M. (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther.1:97-102; Olsen, T. W. et al. (1995), Human scleral permeability:effects of age, cryotherapy, transscleral diode laser, and surgicalthinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903; and Kwak, H. W.and D'Amico, D. J. (1992). Evaluation of the retinal toxicity andpharmacokinetics of dexamethasone after intravitreal injection, Arch.Ophthalmol. 110:259-66.

Additionally, topical, systemic, and periocular glucocorticoid treatmentmust be monitored closely due to toxicity and the long-term side effectsassociated with chronic systemic drug exposure sequelae. Rao, N. A. etal. (1997). Intraocular inflammation and uveitis, In Basic and ClinicalScience Course. Section 9 (1997-1998) San Francisco: American Academy ofOphthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). Theresponse of ocular pressure to corticosteroids, Ophthalmol Clin North Am6:929-89; Skalka, H. W. and Pichal, J. T. (1980). Effect ofcorticosteroids on cataract formation, Arch Ophthalmol 98:1773-7;Renfro, L and Snow, J. S. (1992). Ocular effects of topical and systemicsteroids, Dermatologic Clinics 10:505-12; Bodor, N. et al. (1992). Acomparison of intraocular pressure elevating activity of loteprednoletabonate and dexamethasone in rabbits, Current Eye Research 11:525-30.

U.S. Pat. No. 6,217,895 discusses a method of administering acorticosteroid to the posterior segment of the eye, but does notdisclose a bioerodible implant.

U.S. Pat. No. 5,501,856 discloses controlled release pharmaceuticalpreparations for intraocular implants to be applied to the interior ofthe eye after a surgical operation for disorders in retina/vitreous bodyor for glaucoma.

U.S. Pat. No. 5,869,079 discloses combinations of hydrophilic andhydrophobic entities in a biodegradable sustained release implant, anddescribes a polylactic acid polyglycolic acid (PLGA) copolymer implantcomprising dexamethasone. As shown by in vitro testing of the drugrelease kinetics, the 100-120 μg 50/50 PLGA/dexamethasone implantdisclosed did not show appreciable drug release until the beginning ofthe fourth week, unless a release enhancer, such as HPMC was added tothe formulation.

U.S. Pat. No. 5,824,072 discloses implants for introduction into asuprachoroidal space or an avascular region of the eye, and describes amethylcellulose (i.e. non-biodegradable) implant comprisingdexamethasone. WO 9513765 discloses implants comprising active agentsfor introduction into a suprachoroidal or an avascular region of an eyefor therapeutic purposes.

U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose biodegradable ocularimplants comprising microencapsulated drugs, and describes implantingmicrocapsules comprising hydrocortisone succinate into the posteriorsegment of the eye.

U.S. Pat. No. 5,164,188 discloses encapsulated agents for introductioninto the suprachoroid of the eye, and describes placing microcapsulesand plaques comprising hydrocortisone into the pars plana. U.S. Pat.Nos. 5,443,505 and 5,766,242 discloses implants comprising active agentsfor introduction into a suprachoroidal space or an avascular region ofthe eye, and describes placing microcapsules and plaques comprisinghydrocortisone into the pars plana.

Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine,triamcinolone, and human recombinant tissue plasminogen activator forintraocular management of proliferative vitreoretinopathy (PVR). Zhou,T, et al. (1998). Development of a multiple-drug delivery implant forintraocular management of proliferative vitreoretinopathy, Journal ofControlled Release 55:281-295.

U.S. Pat. No. 6,046,187 discusses methods and compositions formodulating local anesthetic by administering one or moreglucocorticosteroid agents before, simultaneously with or after theadministration of a local anesthetic at a site in a patient.

U.S. Pat. No. 3,986,510 discusses ocular inserts having one or moreinner reservoirs of a drug formulation confined within a bioerodibledrug release rate controlling material of a shape adapted for insertionand retention in the “sac of the eye,” which is indicated as beingbounded by the surfaces of the bulbar conjunctiva of the sclera of theeyeball and the palpebral conjunctiva of the eyelid, or for placementover the corneal section of the eye.

U.S. Pat. No. 6,369,116 discusses an implant with a release modifierinserted in a scleral flap.

EP 0 654256 discusses use of a scleral plug after surgery on a vitreousbody, for plugging an incision.

U.S. Pat. No. 4,863,457 discusses the use of a bioerodible implant toprevent failure of glaucoma filtration surgery by positioning theimplant either in the subconjunctival region between the conjunctivalmembrane overlying it and the sclera beneath it or within the scleraitself within a partial thickness sclera flap.

EP 488 401 discusses intraocular implants, made of certain polylacticacids, to be applied to the interior of the eye after a surgicaloperation for disorders of the retina/vitreous body or for glaucoma.

EP 430539 discusses use of a bioerodible implant which is inserted inthe suprachoroid.

It is known that PLGA co-polymer formulations of a bioerodible polymercomprising an active agent typically release the active agent with acharacteristic sigmoidal release profile (as viewed as time vs percentof total active agent released), that is after a relatively long initiallag period (the first release phase) when little if any active agent isreleased, there is a high positive slope period when most of the activeagent is released (the second release phase) followed by another nearhorizontal (third) release phase, when the drug release reaches aplateau.

It is known in the art that polymer types may be blended to optimizedrug release kinetics. See, Liggins, R. T. and Bent, H. M.,Paclitaxel-loaded poly(L-lactic acid) microspheres 3: blending low andhigh molecular weight polymers to control morphology and drug release;International J of Pharmaceutics 282, 61-71 (2004). However, limitationsin current technology become apparent when attempting to sustain a zeroorder release of a drug at a therapeutically effective concentration foras long as three to six months. In the case of highly water-solubledrugs such as certain proteins or oligonucleotides, polymer loading isusually limited to below 20% w/w due to undesirably high burst releaseprofiles. Excessive burst release of 30-80% of the drug payload withinone or two days not only precludes extended release by wasting drug, butmay also result in undesirable biological effects. Such adverse effectsmay include drug cytotoxicities, biological accommodation involving upor down regulation of specific drug receptors, or off-targeting ofinhibitors such as siRNAs. Other limitations of the current drugdelivery systems include the inability to engineer a “drug holiday”during which time no drug is released for safety reasons and theinability to independently control the release profiles of two or moredrugs, without requiring multiple injections.

Thus, there is a need for a therapeutically effective extended releaseimplant for the treatment of an ocular condition, such as posteriorocular condition. In particular, there is a need for effective deliveryover an extended duration, for example, time periods extending up to 60days, 90 days, 120 days, 6 months, 8 months, 12 months or more,preferably with maintenance of a therapeutic drug level at a desiredposterior ocular region or site and with flexible or adjustable drugrelease characteristics/profiles, optionally including one or more “drugholidays” during which time no drug is released to the patient. Suchextended and flexible delivery of one or more active agents can beadvantageous to prevent recurrence of the inflammatory or otherposterior ocular condition treated. It can also minimize the number ofsurgical interventions required by the patient over time to treat thecondition, as compared to the use of prior implants, such as thosehaving shorter release profiles and/or consistent release profiles.

SUMMARY

The present invention meets these and other needs and provides for adrug delivery system that comprises segmented bioerodible implants thatcan provide for flexible, separate and independent drug releasecharacteristics amongst the individual segments, thereby facilitatingextended drug release for up to three to six months while avoiding highdrug loading or excessive burst release, but permitting variations indrug release profiles.

Definitions

The following terms as used herein have the following meanings:

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means ±10% of the numerical value orrange recited or claimed.

“Active agent” and “drug” are used interchangeably and refer to anysubstance used to treat an ocular condition.

“Bioerodible polymer” means a polymer which degrades in vivo, andwherein erosion of the polymer over time is required to achieve theactive agent release kinetics according to the present invention. Thus,hydrogels such as methylcellulose which act to release drug throughpolymer swelling are specifically excluded from the term “bioerodible(or biodegradable) polymer”. The words “bioerodible” and “biodegradable”are synonymous and are used interchangeably herein.

“Cumulative release profile” means to the cumulative total percent of anactive agent released from an implant into an ocular region or site invivo over time or into a specific release medium in vitro over time.

“Extended” as in “extended period” or “extended release” means for aperiod of time greater than thirty days, preferably for at least 50 days(i.e. for a period of time from 50 days to 365 days), and mostpreferably for at least 60 days. An extended release can persist for ayear or more.

“Glaucoma” means primary, secondary and/or congenital glaucoma. Primaryglaucoma can include open angle and closed angle glaucoma. Secondaryglaucoma can occur as a complication of a variety of other conditions,such as injury, inflammation, vascular disease and diabetes.

“Inflammation-mediated” in relation to an ocular condition means anycondition of the eye which can benefit from treatment with ananti-inflammatory agent, and is meant to include, but is not limited to,uveitis, macular edema, acute macular degeneration, retinal detachment,ocular tumors, fungal or viral infections, multifocal choroiditis,diabetic uveitis, proliferative vitreoretinopathy (PVR), sympatheticophthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, anduveal diffusion.

“Injury” or “damage” are interchangeable and refer to the cellular andmorphological manifestations and symptoms resulting from aninflammatory-mediated condition, such as, for example, inflammation.

“Measured under infinite sink conditions in vitro,” means assays tomeasure drug release in vitro, wherein the experiment is designed suchthat the drug concentration in the receptor medium never exceeds 5% ofsaturation. Examples of suitable assays may be found, for example, inUSP 23; NF 18 (1995) pp. 1790-1798.

“Ocular condition” means a disease, aliment or condition which affectsor involves the eye or one or the parts or regions of the eye, such as aretinal disease. The eye includes the eyeball and the tissues and fluidswhich constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

“Plurality” means two or more.

“Posterior ocular condition” means a disease, ailment or condition whichaffects or involves a posterior ocular region or site such as choroid orsclera (in a position posterior to a plane through the posterior wall ofthe lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e.the optic disc), and blood vessels and nerve which vascularize orinnervate a posterior ocular region or site.

“Steroidal anti-inflammatory agent” and “glucocorticoid” are usedinterchangeably herein, and are meant to include steroidal agents,compounds or drugs which reduce inflammation when administered at atherapeutically effective level.

“Substantially” in relation to the release profile or the releasecharacteristic of an active agent from a bioerodible implant as in thephrase “substantially continuous rate” of the active agent release ratefrom the implant means, that the rate of release (i.e. amount of activeagent released/unit of time) does not vary by more than 100%, andpreferably does not vary by more than 50%, over the period of timeselected (i.e. a number of days). “Substantially” in relation to theblending, mixing or dispersing of an active agent in a polymer, as inthe phrase “substantially homogenously dispersed” means that there areno or essentially no particles (i.e. aggregations) of active agent insuch a homogenous dispersal.

“Suitable for insertion (or implantation) in (or into) an ocular regionor site” with regard to an implant, means an implant which has a size(dimensions) such that it can be inserted or implanted without causingexcessive tissue damage and without unduly physically interfering withthe existing vision of the patient into which the implant is implantedor inserted.

“Therapeutic levels” or “therapeutic amount” means an amount or aconcentration of an active agent that has been locally delivered to anocular region that is appropriate to safely treat an ocular condition soas to reduce or prevent a symptom of an ocular condition.

In one variation, the present invention provides for a drug deliverysystem (DDS) for treating conditions of the eye that comprises asegmented DDS, each segment comprising a bioerodible implant, eachbioerodible implant having a unique drug release profile. In certainvariations, this implant system can include three or more implants, eachof which is formed from a separate poly(lactide) (i.e. PLA) polymer orpoly(lactide-co-glycolide) (i.e. PLGA) copolymer, different polymerblends, or similar polymer blends but with different excipients (in kindor amount) to provide different drug release profiles.

In other variations, bioerodible implants according to the presentinvention are prepared using two or more different bioerodible polymerseach having different release characteristics. In one variation, a firstquantity of the drug or active agent is blended with a first polymercomposition and the resultant material is extruded into an implantsegment and a second quantity of the same or different drug or activeagent is blended with a different polymer composition to form a secondbioerodible implant segment. The resultant implant segments havedifferent release profiles. The implant segments can be prepared andadministered as individual segments, or can be combined into a singlesegmented DDS, wherein the individual segments are encased within anexternal matrix, whereby the individual segments separated from eachother immediately following injection into the patient, such as into thepatient's eye.

The invention encompasses a drug delivery system for treating an ocularcondition, the drug delivery system can comprise: (a) at least twobioerodible implant segments suitable for insertion into an ocularregion or site, each bioerodible implant segment comprising; (i) anactive agent, and; (ii) a bioerodible polymer, wherein each bioerodibleimplant segment can release a therapeutic level of the active agent intothe ocular region or site for a period time between about 30 days andabout 1 year and wherein at least one of the implant segments has a drugrelease profile that is different from at least one other segment. Thebioerodible implant segments can release the therapeutic level of theactive agent into the ocular region or site at a substantiallycontinuous rate in vivo for the desired period of time. The DDScomprising segments of different drug release profiles can release atherapeutic level of the active agent into the ocular region or site ata substantially continuous rate upon implantation in the vitreous for aperiod time between about 50 days and about 1 year or can includeso-called “drug holidays” wherein no drug is released to the ocularregion.

The bioerodible implant can have a weight between about 1 μg and about100 mg and no dimension less than about 0.1 mm and no dimension greaterthan about 20 mm.

A drug delivery system of claim within the scope of the invention cancomprise a plurality of bioerodible implant segments. The active agentcan be substantially homogenously dispersed within the bioerodiblepolymer or the active agent can be associated with the bioerodiblepolymer in the form of particles of active agent and bioerodiblepolymer.

The drug delivery system of the invention can comprise: (a) a pluralityof bioerodible implant segments implantable in a posterior ocular regionor site, each segment comprising; (i) an active agent, and; (ii) abioerodible polymer, wherein the plurality of segments can substantiallycontinuously, or in any desired pattern or profile, release in vivo atherapeutic level of the active agent or a plurality of different activeagents, for a period time between about 5 days and about 1 year. Thisdrug delivery system can comprise: (a) a first segment with a firstrelease characteristic, and; (b) a second implant with a second releasecharacteristic, wherein the first and second release characteristicsdiffer. The release profile of the drug delivery system can correspondto the sum of the first and second release profiles. Alternatively, thisdrug delivery system can comprise: (a) a first segment with a firstrelease characteristic, (b) a second segment with a second releasecharacteristic, and; (c) a third implant with a third releasecharacteristic. The release profile of the drug delivery system cancorrespond to the sum of the first, second and third release profiles.Thus, the drug deliver system can comprise first, second and thirdbioerodible segments, wherein the first segment comprises a firstpolymer component; the second segment comprises a second polymercomponent, and the third segment comprises a third polymer component,wherein the first, second and third polymer components differ withrespect to the mixture of the blended polymers (by type and/or percentmixture).

One method for making an extended release bioerodible implant fortreating an ocular condition can be by: (a) blending and extruding firstactive agent and a first bioerodible polymer composition to form a firstimplant segment; (b) blending and extruding a second active agent with asecond bioerodible polymer composition, to form a second implantsegment, wherein the implants can release a therapeutic level of theactive agents at a substantially continuous rate for a period timebetween about 50 days and about 1 year, but with different profiles withrespect to each other.

The first active agent and the second active agent can be the sameactive agent or the first active agent and the second active agent canbe different active agents. As well, the first polymer composition andthe second polymer composition can comprise the same polymer but withdifferent excipients (in kind and/or amount) or the first polymercomposition and the second polymer composition can comprise differentpolymers, whereby the drug release profiles can be adjusted by adjustingthe ratio of monomers in the polymer blend and/or by, includingappropriate excipients, or amounts of excipients, to modify the drugrelease characteristics.

A method for treating an ocular condition according to our invention cancomprise implanting into an ocular region or site a drug delivery systemset forth herein.

Our invention includes a drug delivery system for treating an ocularcondition. The drug delivery system can comprise a bioerodible implanthaving a plurality of segments, wherein each of the segments comprisesan active agent and (ii) a bioerodible polymer; at least some of thesegments have drug release characteristics different from othersegments; and the segments are joined together (or otherwise associatedwith each other as separate implants which are implanted together) in amanner to permit separation from each other in situ into individualsegments following intraocular implantation of the drug delivery systeminto a patient.

Our invention also includes a drug delivery system for treating anocular condition which comprises a bioerodible implant comprising aplurality of rod-shaped segments, wherein each of the segments comprises(i) an active agent for treating the ocular condition and (ii) abioerodible polymer; at least some of the segments have drug releasecharacteristics different from other that of other segments; thesegments are joined (or associated) together at the ends thereof to forma contiguous rod-shaped implant; and the segments are joined at the endsthereof in a manner to permit separation of the segments from each otherin situ into individual segments following implantation into the ocularregion of a patient.

Our invention also encompasses a drug delivery system for treating anocular condition which comprises a bioerodible implant comprising aplurality of rod-shaped segments, wherein each of the segments comprises(i) an active agent for treating the ocular condition and (ii) abioerodible polymer; at least some of the segments have drug releasecharacteristics different from other of the segments; and at least someof the segments having at least one end thereof having a cut surfacethat is at an angle to the longitudinal axis of less than 90° or havingat least one end which is of beveled shape.

The individual segments can be are joined together at the ends thereofto form a contiguous rod-shaped implant having a longitudinal axis, thesegments being joined together in a matrix comprised of a bioerodiblepolymer in a manner to permit separation of the segments from each otherin situ into individual segments following implantation into the ocularregion of a patient.

The bioerodible polymer of our drug delivery system can comprise atleast one member selected from the group consisting of poly(lactide)polymers and poly(lactide-co-glycolide) copolymers. The implants of ourdrug delivery can further comprise at least one excipient that modifiesthe erosion characteristics of the bioerodible polymer. The excipientcan be a long chain fatty alcohol, cholesterol, or high molecular weightpolyethylene glycol polymers.

The bioerodible polymer can be a poly(D,L-lactide-co-glycolide)copolymer with a monomer ratio in the range of 50:50 to 85:15.Preferably, at least one of the segments can release all activeingredient within one week of implantation and at least one of thesegments can begin releasing the active ingredient after one weekpost-implantation. Alternately, a at least one of the segments can beginreleasing active ingredient at 12 weeks post-implantation or at leastone of the segments releases the active ingredient from 3 to 6 monthspost-implantation.

The active ingredient can be released from one of the segments withinthe first week after implantation, but with no drug released from any ofthe segments for some period of time after the first weekpost-implantation.

At least some of the segments can comprise a first active ingredient andother of the segments can comprise a second active ingredient. Each ofthe segments can have drug release characteristics different from all ofthe other of the segments that comprise the implant.

The active ingredient can be a steroid, an anti-inflammatory compound,or an anti-angiogenesis compound. The active ingredient can, forexample, be methotrexate, retinoic acid, aspirin, diclofenac,flurbiprofen, ibuprofen, ketorolac, naproxen, uprofen, dexamethasone,cortisone, fluocinolone, hydrocortisone, methylprednisolone,prednisolone, prednisone, or triamcinolone.

Our invention includes a method of manufacturing a drug delivery systemwhich comprises a bioerodible implant by: blending a first active agentwith a first bioerodible polymer to form a first active agent polymermixture; forming the first active agent polymer mixture into a rodshaped first implant segment having a longitudinal axis; blending asecond active agent with a second bioerodible polymer to form a secondactive agent polymer mixture; and forming at least some of the segmentswith at least one end thereof having a cut surface that is at an angleto the longitudinal axis of less than 90° or has a beveled shape. Thesegments can be joined at the ends thereof to permit separation fromeach other in situ into individual segments following implantation intoa patient. Each of the segments can be formed with at least one endhaving a cut surface that is at an angle to the longitudinal axis ofless than 90° or one end having a beveled shaped surface. Thebioerodible polymer can be a poly(lactide) polymer andpoly(lactide-co-glycolide) copolymer. At least one excipient thatmodifies the erosion characteristics of the bioerodible polymer can beblended with the active agent and the bioerodible polymer.

DRAWINGS

FIG. 1 depicts a typical drug delivery system in the prior art.

FIG. 2 depicts a segmented drug delivery system implant according to theinvention.

FIG. 3 depicts another segmented drug delivery system implant accordingto the invention.

DESCRIPTION

The present invention is based upon the discovery of a drug deliverysystem (DDS) comprised of segmented bioerodible implants whereby eachsegment can release a therapeutic amount of an active agent for anextended period of time to treat an ocular condition with each segmentcapable of having an independent drug release profile that is differentfrom the other segments. The present invention encompasses biodegradableocular implants and implant systems and methods of using such implantsand implant systems for treating ocular conditions. The implants can beformed to be monolithic, that is the active agent is homogenouslydistributed or dispersed throughout the biodegradable polymer matrix.Additionally, the implants can be formed to release an active agent intoan ocular region of the eye over various extended release time periods.Thus, the active agent can be released from implants made according tothe present invention for an extended periods of time of approximately60 days or more, 90 days or more, 120 days or more, 6 months or more, 8months or more or 12 months or more.

Biodegradable Implants for Treating an Ocular Condition

The implants of the present invention can include an active agent mixedwith or dispersed within a biodegradable polymer. The implantcompositions can vary according to the preferred drug release profile,the particular active agent used, the ocular condition being treated,and the medical history of the patient. Active agents that may be usedinclude, but are not limited to (either by itself in an implant withinthe scope of the present invention or in combination with another activeagent): ace-inhibitors, endogenous cytokines, agents that influencebasement membrane, agents that influence the growth of endothelialcells, adrenergic agonists or blockers, cholinergic agonists orblockers, aldose reductase inhibitors, analgesics, anesthetics,antiallergics, anti-inflammatory agents, antihypertensives, pressors,antibacterials, antivirals, antifungals, antiprotozoals,anti-infectives, antitumor agents, antimetabolites, antiangiogenicagents, tyrosine kinase inhibitors, antibiotics such as aminoglycosidessuch as gentamycin, kanamycin, neomycin, and vancomycin; amphenicolssuch as chloramphenicol; cephalosporins, such as cefazolin HCl;penicillins such as ampicillin, penicillin, carbenicillin, oxycillin,methicillin; lincosamides such as lincomycin; polypeptide antibioticssuch as polymixin and bacitracin; tetracyclines such as tetracycline;quinolones such as ciproflaxin, etc.; sulfonamides such as chloramine T;and sulfones such as sulfanilic acid as the hydrophilic entity,anti-viral drugs, e.g. acyclovir, gancyclovir, vidarabine,azidothymidine, dideoxyinosine, dideoxycytosine, dexamethasone,ciproflaxin, water soluble antibiotics, such as acyclovir, gancyclovir,vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine;epinephrine; isoflurophate; adriamycin; bleomycin; mitomycin; ara-C;actinomycin D; scopolamine; and the like, analgesics, such as codeine,morphine, ketorolac, naproxen, etc., an anesthetic, e.g. lidocaine;.beta.-adrenergic blocker or ⊕-adrenergic agonist, e.g. ephedrine,epinephrine, etc.; aldose reductase inhibitor, e.g. epalrestat,ponalrestat, sorbinil, tolrestat; antiallergic, e.g. cromolyn,beclomethasone, dexamethasone, and flunisolide; colchicine, anthelminticagents, e.g. ivermectin and suramin sodium; antiamebic agents, e.g.chloroquine and chlortetracycline; and antifungal agents, e.g.amphotericin, etc., anti-angiogenesis compounds such as anecortaveacetate, retinoids such as tazarotene, anti-glaucoma agents, such asbrimonidine (Alphagan and Alphagan P), acetazolamide, bimatoprost(Lumigan), timolol, mebefunolol; memantine; alpha-2 adrenergic receptoragonists; 2-methoxyestradiol; anti-neoplastics, such as vinblastine,vincristine, interferons; alpha, beta and gamma, antimetabolites, suchas folic acid analogs, purine analogs, and pyrimidine analogs;immunosuppressants such as azathioprine, cyclosporine and mizoribine;miotic agents, such as carbachol, mydriatic agents such as atropine,etc., protease inhibitors such as aprotinin, camostat, gabexate,vasodilators such as bradykinin, etc., and various growth factors, suchepidermal growth factor, basic fibroblast growth factor, nerve growthfactors, and the like.

In one variation the active agent is methotrexate. In another variation,the active agent is a retinoic acid. In another variation, the activeagent is an anti-inflammatory agent such as a nonsteroidalanti-inflammatory agent. Nonsteroidal anti-inflammatory agents that maybe used include, but are not limited to, aspirin, diclofenac,flurbiprofen, ibuprofen, ketorolac, naproxen, and suprofen. In a furthervariation, the anti-inflammatory agent is a steroidal anti-inflammatoryagent, such as dexamethasone.

Steroidal Anti-Inflammatory Agents

The steroidal anti-inflammatory agents that may be used in the ocularimplants include, but are not limited to, 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide, and any of their derivatives.

In one embodiment, cortisone, dexamethasone, fluocinolone,hydrocortisone, methylprednisolone, prednisolone, prednisone, andtriamcinolone, and their derivatives, are preferred steroidalanti-inflammatory agents. In another preferred variation, the steroidalanti-inflammatory agent is dexamethasone. In another variation, thebiodegradable implant includes a combination of two or more steroidalanti-inflammatory agents.

The active agent, such as a steroidal anti-inflammatory agent, cancomprise from about 10% to about 90% by weight of the implant. In onevariation, the agent is from about 40% to about 80% by weight of theimplant. In one embodiment, the agent comprises about 60% by weight ofthe implant. In another embodiment of the present invention, the agentcan comprise about 50% by weight of the implant.

Biodegradable Polymers

In one variation, the active agent can be homogeneously dispersed in thebiodegradable polymer of the implant. The implant can be made, forexample, by a sequential or double extrusion method. The selection ofthe biodegradable polymer used can vary with the desired releasekinetics, patient tolerance, the nature of the disease to be treated,and the like. Polymer characteristics that are considered include, butare not limited to, the biocompatibility and biodegradability at thesite of implantation, compatibility with the active agent of interest,and processing temperatures. The biodegradable polymer matrix usuallycomprises at least about 10, at least about 20, at least about 30, atleast about 40, at least about 50, at least about 60, at least about 70,at least about 80, or at least about 90 weight percent of the implant.In one variation, the biodegradable polymer matrix comprises about 40%to 50% by weight of the implant.

Biodegradable polymers which can be used include, but are not limitedto, polymers made of monomers such as organic esters or ethers, whichwhen degraded result in physiologically acceptable degradation products.Anhydrides, amides, orthoesters, or the like, by themselves or incombination with other monomers, may also be used. The polymers aregenerally condensation polymers. The polymers can be crosslinked ornon-crosslinked. If crosslinked, they are usually not more than lightlycrosslinked, and are less than 5% crosslinked, usually less than 1%crosslinked.

For the most part, besides carbon and hydrogen, the polymers willinclude oxygen and nitrogen, particularly oxygen. The oxygen may bepresent as oxy, e.g., hydroxy or ether, carbonyl, e.g.,non-oxo-carbonyl, such as carboxylic acid ester, and the like. Thenitrogen can be present as amide, cyano, and amino. An exemplary list ofbiodegradable polymers that can be used are described in Heller,Biodegradable Polymers in Controlled Drug Delivery, In: “CRC CriticalReviews in Therapeutic Drug Carrier Systems”, Vol. 1. CRC Press, BocaRaton, Fla. (1987).

Of particular interest are polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, and polysaccharides. Included amongthe polyesters of interest are homo- or copolymers of D-lactic acid,L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, andcombinations thereof. Copolymers of glycolic and lactic acid are ofparticular interest, where the rate of biodegradation is controlled bythe ratio of glycolic to lactic acid. The percent of each monomer inpoly(lactic-co-glycolic)acid (PLGA) copolymer may be 0-100%, about15-85%, about 25-75%, or about 35-65%. In certain variations, 25/75 PLGAand/or 50/50 PLGA and/or 75/25 PLGA, and/or 85/15 PLGA copolymers areused. In other variations, PLGA copolymers are used in conjunction withpolylactide polymers.

Biodegradable polymer matrices that include mixtures of hydrophilic andhydrophobic ended PLGA may also be employed, and are useful inmodulating polymer matrix degradation rates. Hydrophobic ended (alsoreferred to as capped or end-capped) PLGA has an ester linkagehydrophobic in nature at the polymer terminus. Typical hydrophobic endgroups include, but are not limited to alkyl esters and aromatic esters.Hydrophilic ended (also referred to as uncapped) PLGA has an end grouphydrophilic in nature at the polymer terminus. PLGA with a hydrophilicend groups at the polymer terminus degrades faster than hydrophobicended PLGA because it takes up water and undergoes hydrolysis at afaster rate (Tracy et al., Biomaterials 20:1057-1062 (1999)). Examplesof suitable hydrophilic end groups that may be incorporated to enhancehydrolysis include, but are not limited to, carboxyl, hydroxyl, andpolyethylene glycol. The specific end group will typically result fromthe initiator employed in the polymerization process. For example, ifthe initiator is water or carboxylic acid, the resulting end groups willbe carboxyl and hydroxyl. Similarly, if the initiator is amonofunctional alcohol, the resulting end groups will be ester orhydroxyl.

Excipients

The segments are preferably formulated with different polymer blends, orof similar blends but with different excipients, and are designed toerode at different rates in situ. The present invention offers theformulator additional degrees of freedom, thereby facilitating extendedrelease for as long as three to six months while avoiding high drugloading and excessive burst release of very water-soluble drugs.

Excipients that may be incorporated into some or all of these DDSsegments include poorly water-soluble molecules such as long chain fattyalcohols, cholesterol, or high molecular weight polyethylene glycolpolymers. These excipients may fill voids and pores in the polymermatrix and retard undesirable burst release of water-soluble drugs.Concentrations of certain excipients in one or more segments candramatically slow drug release rates, an effect which is advantageousfor designing optimum sustained release kinetics.

Aliphatic alcohols (also known synonymously as fatty alcohols or as longchain alcohols or as long chain fatty alcohols) are predominatelystraight chain organic molecules with an even number of carbon atomsderived from natural fats and oils. Aliphatic alcohols can be convertedto or derived from fatty acids and fatty aldehydes. It is known to usethe smaller aliphatic alcohols as additives in cosmetics and food, andas industrial solvents. Some larger aliphatic alcohols have been used asbiofuels.

Due to their amphipathic nature, aliphatic alcohols can behave asnonionic surfactants and find use as emulsifiers, emollients andthickeners in the cosmetics and food industries. Additionally, aliphaticalcohols are a common component of waxes, mostly as esters with fattyacids but also as alcohols themselves.

Natural Fatty alcohols can be derived from natural fats and oils and arehigh molecular straight chain primary alcohols. They include lauryl(C12), myristyl (C14), Cetyl (or palmityl: C16), stearyl (C18), Oleyl(C18, unsaturated), and Linoleyl (C18, polyunsaturated) alcohols.Synthetic fatty alcohols equivalent physically and chemically to naturalalcohols can be obtained from oleochemical sources such as coconut andpalm kernel oil.

Aliphatic alcohols include:

-   capryl alcohol (1-octanol)—8 carbon atoms-   pelargonic alcohol (1-nonanol)—9 carbon atoms-   capric alcohol (1-decanol, decyl alcohol)—10 carbon atoms-   lauryl alcohol (1-dodecanol)—12 carbon atoms-   myristyl alcohol (1-tetradecanol)—14 carbon atoms-   cetyl alcohol (1-hexadecanol: C₁₆H₃₄O)—16 carbon atoms and has a    molecular weight of 242.45-   palmitoleyl alcohol (cis-9-hexadecan-1-ol)—16 carbon atoms,    unsaturated, CH₃(CH₂)₅CH═CH(CH₂)₈OH-   stearyl alcohol (1-octadecanol)—18 carbon atoms-   isostearyl alcohol (16-methylheptadecan-1-ol)—18 carbon atoms,    branched, (CH₃)₂CH—(CH₂)₁₅OH-   elaidyl alcohol (9E-octadecen-1-ol)—18 carbon atoms, unsaturated,    CH₃(CH₂)₇CH═CH(CH₂)₈OH-   oleyl alcohol (cis-9-octadecen-1-ol)—18 carbon atoms, unsaturated-   linoleyl alcohol (9Z, 12Z-octadecadien-1-ol)—18 carbon atoms,-   polyunsaturated elaidolinoleyl alcohol (9E,    12E-octadecadien-1-ol)—18 carbon atoms, polyunsaturated-   linolenyl alcohol (9Z, 12Z, 15Z-octadecatrien-1-ol)—18 carbon atoms,    polyunsaturated-   elaidolinolenyl alcohol (9E, 12E, 15-E-octadecatrien-1-ol)—18 carbon    atoms, polyunsaturated-   ricinoleyl alcohol (12-hydroxy-9-octadecen-1-ol)—18 carbon atoms,    unsaturated, diol, CH₃(CH₂)₅CH(OH)CH₂CH═CH(CH₂)₈OH-   arachidyl alcohol (1-eicosanol)—20 carbon atoms-   behenyl alcohol (1-docosanol)—22 carbon atoms-   erucyl alcohol (cis-13-docosen-1-ol)—22 carbon atoms, unsaturated,    CH₃(CH₂)₇CH═CH(CH₂)₁₂OH-   lignoceryl alcohol (1-tetracosanol)—24 carbon atoms-   ceryl alcohol (1-hexacosanol)—26 carbon atoms-   montanyl alcohol, cluytyl alcohol (1-octacosanol)—28 carbon atoms-   myricyl alcohol, melissyl alcohol (1-triacontanol)—30 carbon atoms,    and;-   geddyl alcohol (1-tetratriacontanol)—34 carbon atoms.

Behenyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosanol,montanyl alcohol, 1-nonacosanol, myricyl alcohol, 1-dotriacontanol, andgeddyl alcohol are together classified as policosanol, with montanylalcohol and myricyl alcohol being the most abundant.

1-eicosanol (arachidyl alcohol) has the formula CH₃(CH₂)₁₈CH₂OH and amolecular weight of 298.55. Synonyms are 1-Icosanol; Icosan-1-ol;Icosanol; arachidic alcohol; eicosyl alcohol; 1-prydroxyeicosane, and;eicosanol-(1). It is a white solid with a melting point of 64-66° C.

Additional Agents

Other agents may be employed in the formulation for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Preservatives which may be used include, but are not limitedto, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. Examples of buffering agents that may be employed include, butare not limited to, sodium carbonate, sodium borate, sodium phosphate,sodium acetate, sodium bicarbonate, and the like, as approved by the FDAfor the desired route of administration. Electrolytes such as sodiumchloride and potassium chloride may also be included in the formulation.

The biodegradable ocular implants can also include additionalhydrophilic or hydrophobic compounds that accelerate or retard releaseof the active agent. Additionally, release modulators such as thosedescribed in U.S. Pat. No. 5,869,079 can be included in the implants.The amount of release modulator employed will be dependent on thedesired release profile, the activity of the modulator, and on therelease profile of the glucocorticoid in the absence of modulator. Wherethe buffering agent or release enhancer or modulator is hydrophilic, itmay also act as a release accelerator. Hydrophilic additives act toincrease the release rates through faster dissolution of the materialsurrounding the drug particles, which increases the surface area of thedrug exposed, thereby increasing the rate of drug diffusion. Similarly,a hydrophobic buffering agent or enhancer or modulator can dissolve moreslowly, slowing the exposure of drug particles, and thereby slowing therate of drug diffusion.

Release Kinetics

An implant within the scope of the present invention can be formulatedwith particles of an active agent dispersed within a biodegradablepolymer matrix. Without being bound by theory, it is believed that therelease of the active agent can be achieved by erosion of thebiodegradable polymer matrix and by diffusion of the particulate agentinto an ocular fluid, e.g., the vitreous, with subsequent dissolution ofthe polymer matrix and release of the active agent. Factors whichinfluence the release kinetics of active agent from the implant caninclude such characteristics as the size and shape of the implant, thesize of the active agent particles, the solubility of the active agent,the ratio of active agent to polymer(s), the method of manufacture, thesurface area exposed, and the erosion rate of the polymer(s). Therelease kinetics achieved by this form of active agent release aredifferent than that achieved through formulations which release activeagents through polymer swelling, such as with crosslinked hydrogels. Inthat case, the active agent is not released through polymer erosion, butthrough polymer swelling and drug diffusion, which releases agent asliquid diffuses through the pathways exposed.

The release rate of the active agent can depend at least in part on therate of degradation of the polymer backbone component or componentsmaking up the biodegradable polymer matrix. For example, condensationpolymers may be degraded by hydrolysis (among other mechanisms) andtherefore any change in the composition of the implant that enhanceswater uptake by the implant will likely increase the rate of hydrolysis,thereby increasing the rate of polymer degradation and erosion, and thusincreasing the rate of active agent release.

The release kinetics of the implants of the present invention can bedependent in part on the surface area of the implants. A larger surfacearea exposes more polymer and active agent to ocular fluid, causingfaster erosion of the polymer matrix and dissolution of the active agentparticles in the fluid. Therefore, the size and shape of the implant mayalso be used to control the rate of release, period of treatment, andactive agent concentration at the site of implantation. At equal activeagent loads, larger implants will deliver a proportionately larger dose,but depending on the surface to mass ratio, may possess a slower releaserate. For implantation in an ocular region, the total weight of theimplant preferably ranges, e.g., from about 100 μg to about 15 mg.Alternatively, the implant rages from about 300 μg to about 10 mg, orfrom about 500 μg to about 5 mg. In a particular embodiment of thepresent invention the weight of an implant is between about 500 μg andabout 2 mg, such as between about 500 μg and about 1 mg.

Segmenting Implants to Affect Release Kinetics

According to the invention, the release kinetics can also be altered byproducing the implant segments with cut ends that are different from a90° angle. FIG. 1 shows implant segments prepared in a rod shape withstraight ends cut at a 90° angle. Alternatively, one or both ends of animplant segment can be prepared as beveled or cut at less that a 90°angle, as shown in FIG. 3. Of course, segments can be prepared withcombinations of different cut end shapes, modified to produce thedesired modified kinetic characteristics based upon the altered surfacearea of the segments. An implant segment end can be angulated so as tofacilitate implant segments (when a plurality of implant segments areimplanted) easily sliding past one another so that all implant segmentscan align side by side in the vitreous, instead of the implants aligningas a single line of implants in the vitreous.

The implant segments according to the invention can be prepared andadministered as distinct separate and independent segments, or as asingle segmented DDS wherein the individual segments are encased in oneexternal matrix. If prepared as a single DDS, the external matrix cancomprise quickly erodible PLA or PLGA polymers (such as RG502H, RG503Hor RG504H, discussed below) so that immediately upon administration thesegments separate from each other. A quickly erodible matrix can also beprepared by incorporation into two matrix of very water solublemolecules (so-called “pore formers”) such as mannitol (e.g. 5% w/w).

The bioerodible implants are typically solid, and may be formed asparticles, sheets, patches, plaques, films, discs, fibers, rods, and thelike, or may be of any size or shape compatible with the selected siteof implantation, as long as the implants have the desired releasekinetics and deliver an amount of active agent that is therapeutic forthe intended medical condition of the eye. The upper limit for theimplant size will be determined by factors such as the desired releasekinetics, toleration for the implant at the site of implantation, sizelimitations on insertion, and ease of handling. For example, thevitreous chamber is able to accommodate relatively large rod-shapedimplants, generally having diameters of about 0.05 mm to 3 mm and alength of about 0.5 to about 10 mm. In one variation, the rods havediameters of about 0.1 mm to about 1 mm. In another variation, the rodshave diameters of about 0.3 mm to about 0.75 mm. In yet a furthervariation, other implants having variable geometries but approximatelysimilar volumes may also be used.

The proportions of active agent, polymer, and any other modifiers may beempirically determined by formulating several implants with varyingproportions. A USP approved method for dissolution or release test canbe used to measure the rate of release (USP 23; NF 18 (1995) pp.1790-1798). For example, using the infinite sink method, a weighedsample of the drug delivery device is added to a measured volume of asolution containing 0.9% NaCl in water, where the solution volume willbe such that the drug concentration after release is less than 20%, andpreferably less than 5%, of saturation. The mixture is maintained at 37°C. and stirred slowly to ensure drug diffusion after bioerosion. Theappearance of the dissolved drug as a function of time may be followedby various methods known in the art, such as spectrophotometrically,HPLC, mass spectroscopy, etc.

Therapeutic Use

Examples of ocular conditions which can be treated by the implants andmethods of the invention include, but are not limited to, glaucoma,uveitis, macular edema, macular degeneration, retinal detachment,posterior ocular tumors, fungal or viral infections, multifocalchoroiditis, diabetic retinopathy, proliferative vitreoretinopathy(PVR), sympathetic opthalmia, Vogt Koyanagi-Harada (VKH) syndrome,histoplasmosis, uveal diffusion, and vascular occlusion. In onevariation, the implants are particularly useful in treating such medicalconditions as uveitis, macular edema, vascular occlusive conditions,proliferative vitreoretinopathy (PVR), and various other retinopathies.

Methods of Implantation

The biodegradable implants can be inserted into the eye by a variety ofmethods, including placement by forceps, by trocar, or by other types ofapplicators, after making an incision in the sclera. In some instances,a trocar or applicator may be used without creating an incision. In apreferred variation, a hand held applicator is used to insert one ormore biodegradable implants into the eye. The hand held applicatortypically comprises an 18-30 GA stainless steel needle, a lever, anactuator, and a plunger. Suitable devices for inserting an implant orimplants into a posterior ocular region or site includes those disclosedin U.S. patent application Ser. No. 10/666,872.

The method of implantation generally first involves accessing the targetarea within the ocular region with the needle, trocar or implantationdevice. Once within the target area, e.g., the vitreous cavity, a leveron a hand held device can be depressed to cause an actuator to drive aplunger forward. As the plunger moves forward, it can push the implantor implants into the target area (i.e. the vitreous).

Methods for Making Implants

Various techniques may be employed to make implants within the scope ofthe present invention. Useful techniques include phase separationmethods, interfacial methods, extrusion methods, compression methods,molding methods, injection molding methods, heat press methods and thelike.

Choice of the technique, and manipulation of the technique parametersemployed to produce the implants can influence the release rates of thedrug. Room temperature compression methods result in an implant withdiscrete microparticles of drug and polymer interspersed. Extrusionmethods result in implants with a progressively more homogenousdispersion of the drug within a continuous polymer matrix, as theproduction temperature is increased.

The use of extrusion methods allows for large-scale manufacture ofimplants and results in implants with a homogeneous dispersion of thedrug within the polymer matrix. When using extrusion methods, thepolymers and active agents that are chosen are stable at temperaturesrequired for manufacturing, usually at least about 50° C. Extrusionmethods use temperatures of about 25° C. to about 150° C., morepreferably about 60° C. to about 130° C.

Different extrusion methods may yield implants with differentcharacteristics, including but not limited to the homogeneity of thedispersion of the active agent within the polymer matrix. For example,using a piston extruder, a single screw extruder, and a twin screwextruder will generally produce implants with progressively morehomogeneous dispersion of the active. When using one extrusion method,extrusion parameters such as temperature, extrusion speed, die geometry,and die surface finish will have an effect on the release profile of theimplants produced.

In one variation of producing implants by a piston extrusion methods,the drug and polymer are first mixed at room temperature and then heatedto a temperature range of about 60° C. to about 150° C., more usually toabout 100° C. for a time period of about 0 to about 1 hour, more usuallyfrom about 0 to about 30 minutes, more usually still from about 5minutes to about 15 minutes, and most usually for about 10 minutes. Theimplants are then extruded at a temperature of about 60° C. to about130° C., preferably at a temperature of about 90° C.

In an exemplary screw extrusion method, the powder blend of active agentand polymer is added to a single or twin screw extruder preset at atemperature of about 80° C. to about 130° C., and directly extruded as afilament or rod with minimal residence time in the extruder. Theextruded filament or rod is then cut into small implants having theloading dose of active agent appropriate to treat the medical conditionof its intended use.

Implant systems according to the invention can include a combination ofa number of bioerodible implant segments, each segment having uniquepolymer compositions and drug release profiles that when co-administeredprovide for an extended continuous release of drug. Further, theachieved continuous release of drug is both prolonged and distinct fromthe release profile that would occur with a single implant consisting ofa blend of the polymers. For example, to achieve continuous release ofat least 120 days, three individual implants made of separate polymercompositions that have fast, medium and slow release characteristics canbe employed, with the fast release implant releasing most of the drugfrom 0-60 days, the medium release implant releasing most of the drugfrom 60-100 days, and the slow release implant releasing most of thedrug from 100 days on. Examples of fast release implants include thosemade of certain lower molecular weight, fast degradation profilepolylactide polymers, such as R104 made by Boehringer Ingelheim GmbH,Germany, which is a poly(D,L-lactide) with a molecular weight of about3,500. Examples of medium release implants include those made of certainmedium molecular weight, intermediate degradation profile PLGAco-polymers, such as RG755 made by Boehringer Ingelheim GmbH, Germany,which is a poly(D,L-lactide-co-glycolide with wt/wt 75% lactide:25%glycolide, a molecular weight of about 40,000 and an inherent viscosityof 0.50 to 0.70 dl/g. Examples of slow release implants include thosemade of certain other high molecular weight, slower degradation profilepolylactide polymers, such as R203/RG755 made by Boehringer IngelheimGmbH, Germany, for which the molecular weight is about 14,000 for R203(inherent viscosity of 0.25 to 0.35 dl/g) and about 40,000 for RG755.When administered together, these implants provide for an extendcontinuous release of drug over a period of at least 120 days in vitrowhich can result in sustained drug levels (concentration) of at leastabout 5-10 ng dexamethasone equivalent/mL in the vitreous (i.e. in vivo)for up to about 240 days.

Individual bioerodible implant segments with extended or variablerelease profiles can also be prepared according to the invention usingtwo or more different bioerodible polymers each having different releasecharacteristics. In one such method, particles of a drug or active agentare blended with a first polymer and extruded to form a filament or rod.This filament or rod is then itself broken first into small pieces andthen further ground into particles with a size (diameter) between about30 μm and about 50 μm, which are then blended with an additionalquantities of the drug or active agent and a second polymer. This secondmixture is then extruded into filaments or rods which are then cut tothe appropriate size to form the final implant. The resultant implanthas a release profile different than that of an implant segment createdby initially blending the two polymers together and then extruding it.It is posited that formed implant includes initial particles of the drugand first polymer having certain specific release characteristics boundup in the second polymer and drug blend that itself has specific releasecharacteristics that are distinct from the first.

Examples of implants include those formed with RG755, R203, RG503,RG502, RG 502H as the first polymer, and RG502, RG 502H as the secondpolymer. Other polymers that can be used include PDL (poly(D,L-lactide))and PDLG (poly(D,L-lactide-co-glycolide)) polymers available from PURACAmerica, Inc. Lincolnshire, Ill. Poly(caprolactone) polymers can also beused. The characteristics of the specified polymers are (1) RG755 has amolecular weight of about 40,000, a lactide content (by weight) of 75%,and a glycolide content (by weight) of 25%; (2) R203 has a molecularweight of about 14,000, and a lactide content of 100%; (3) RG503 has amolecular weight of about 28,000, a lactide content of 50%, and aglycolide content of 50%; (4) RG502 has a molecular weight of about11,700 (inherent viscosity of 0.16 to 0.24 dl/g), a lactide content of50%, and a glycolide content of 50%, and; (5) RG502H has a molecularweight of about 8,500, a lactide content of 50%, a glycolide content of50% and free acid at the end of polymer chain.

Generally, if inherent viscosity is 0.16 the molecular weight is about6,300, and if the inherent viscosity is 0.28 the molecular weight isabout 20,700. It is important to note that all polymer molecular weightsset forth herein are averaged molecular weights in Daltons.

Examples of PLGA-type polymers that may be used for some or all of thesesegments include, but are not limited to, those shown in Table 1.

TABLE 1 Examples of Useful Biodegradable Polymers Approximate BoehringerErosion Time in Ingelheim Catalog Polymer Name vivo Numberpoly(D,L-lactide-co-glycolide) 1 month RG 502H, 503H, 50:50 504Hpoly(D,L-lactide-co-glycolide) 2 months RG 752 75:25poly(D,L-lactide-co-glycolide) 3-4 months LG 857 85:15

According to our invention continual or substantially continual releaseof drug at levels corresponding to at least 10 ng/ml of dexamethasone ordexamethasone equivalent for at least 60 days can be achieved.

In one useful embodiment, polymer segments may be simple rod shapes withstraight ends cut at a 90° angle (FIG. 2). In another embodiment, theends are beveled or shaped in a manner that facilitates separation ofthe segments immediately following injection, for example into thevitreous chamber of an eye (FIG. 3). Such a separation is advantageousto the patient since it avoids or minimizes any obscuration or shadowingin the visual field that commonly occurs upon installation of a single,long cylindrical implant. In addition, separation of polymer segmentsupon injection facilitates a more uniform diffusion of drug into thevitreous chamber, thereby avoiding high local concentrations of eitherdrug or degraded polymer components (e.g., lactic and glycolic acids),any of which could increase cytotoxicity. Thus, for example, a drugdelivery system comprised of a plurality (such as three) segments, eachhaving at least one beveled end, can be administered to a patient's eyewith a standard application, and the individual segments will not stayarranged in one longitudinal system in the patient's eye. The individualsegments, instead, can move to positions near or next to each other.Administration of a plurality of segments, all having flat ends, tendsto result in the administration of a longitudinally continuous line ofsegments, which can obscure the patient's vision.

A multi-segmented cylindrical device composed of a PLGA polymer has beendescribed (Zhou, T. et al, Development of a multiple-drug deliveryimplant for intraocular management of proliferative vitreoretinopathy, Jof Controlled Release 55, 281-295, 1998) that allows for simultaneous,multiple drug release. However, this publication describes a single,long, contiguous cylinder with a series of internal compartments that isimpractical for implantation in the vitreous cavity for reasonsmentioned above. The present invention allows for controlled delivery ofmultiple drugs from multiple independent polymer segments, each with itsown release kinetics tailored to the therapeutic profile of the activeingredient.

The present invention also allows for the design and preparation of aDDS the provides episodic bursts of drug followed by a drug “holiday”which drug delivery pattern may be advantageous for safety reasons,e.g., when the incorporated drug is a potent steroid. In another usefulembodiment, three segments can contain the same drug. For example,Segment #1 provides a loading dose by releasing all incorporated drugwithin one week post-injection, segment #2 releases all drug between thesecond and sixth week, and segment #3 starts releasing drug only at 12weeks. Intentionally, no drug is released between the sixth and twelfthweeks.

In yet another embodiment, segments #1 and #3 can contain drug A whilesegment #2 contains drug B. By choosing the appropriate polymer blendsand excipients, these three segments will release their drug separatelyand at different, predetermined times.

EXAMPLES

The following examples illustrate aspects and embodiments of theinvention.

Example 1 Preparation of Dexamethasone Three Implant Extended ReleaseSystem

A bioerodible implant system for extended delivery of dexamethasone ismade by mixing the active agent dexamethasone (Pharmacia Corp., Peapack,N.J.) separately with each of the following three different polymers:

1. poly (D,L-lactide-co-glycolide) as a 50:50 (wt %/wt %) blend oflactide:glycolide (RG502H, RG503H or RG504H, Boehringer Ingelheim GmbH,Germany),

2. poly(D,L-lactide-co-glycolide) as a 75:25 (wt %/wt %) blend oflactide:glycolide (RG752, Boehringer Ingelheim GmbH, Germany), and;

3. poly (D,L-lactide-co-glycolide) as a 85:15 (wt %/wt %) blend oflactide:glycolide) (LG857, Boehringer Ingelheim GmbH, Germany), so as toobtain three different dexamethasone-polymer mixes.

The polymers noted above are poly(lactide-co-glycolide) co-polymers. Themolecular weight of RG755 is about 40,000.

The dexamethasone and one of the three polymers specified above werethoroughly mixed at a ratio of 50/50 by weight ratio of dexamethasoneand each of the three polymers.

Each of the three separate batches of the three dexamethasone-polymerblends are then fed into a single-piston thermal extruder and threedifferent extruded dexamethasone-polymer filaments are thereby made. Thefilaments are further processed to obtain individual segments(implants), each segment being about a 1 mg implant containingapproximately 0.5 mg of dexamethasone. The three implant segment systemconsists of one of each of the 1 mg implants for each of the threepolymer mixtures which are combined separately with 0.5 mg ofdexamethasone). The total dexamethasone concentration in the combinedthree implants is about 1.5 mg, as of the three implants weighed about 1mg and each of the three implants contained about 50% by weightdexamethasone. A three implant dexamethasone extended release system isthereby made.

Example 2 Treatment of an Ocular Condition with an Anti-InflammatoryActive Agent Extended Release System

An extended release implant system can be used to treat an ocularcondition. The implant can contain a steroid, such an anti-inflammatorysteroid, such as dexamethazone as the active agent. Alternately or inaddition, the active agent can be a non-steroidal anti-inflammatory,such as ketorolac (available from Allergan, Irvine, Calif. as ketorolactromethamine ophthalmic solution, under the tradename Acular). Thus, forexample, a dexamethasone or ketorolac extended release implant system ofExample 1 can be implanted into an ocular region or site (i.e. into thevitreous) of a patient with an ocular condition for a desiredtherapeutic effect. The ocular condition can be an inflammatorycondition such as uveitis or the patient can be afflicted with one ormore of the following afflictions: macular degeneration (includingnon-exudative age related macular degeneration and exudative age relatedmacular degeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (including cystoid macular edema anddiabetic macular edema); Behcet's disease, diabetic retinopathy(including proliferative diabetic retinopathy); retinal arterialocclusive disease; central retinal vein occlusion; uveitic retinaldisease; retinal detachment; retinopathy; an epiretinal membranedisorder; branch retinal vein occlusion; anterior ischemic opticneuropathy; non-retinopathy diabetic retinal dysfunction, retinitispigmentosa and glaucoma. The implant(s) can be inserted into thevitreous using known procedures (trocar implantation). The implant(s)can release a therapeutic amount of, for example the dexamethazone orthe ketorolac for an extended period of time to thereby treat a symptomof the ocular condition.

Example 3 Preparation and Therapeutic Use of an Anti-AngiogenesisExtended Release Implant(s)

An implant to treat an ocular condition according to the presentinvention can contain a steroid, such an anti-angiogenesis steroid, suchas an anecortave, as the active agent. Thus, a bioerodible implantsystem for extended delivery of anecortave acetate (an angiostaticsteroid) can be made using the method of Example 1, but with use ofanecortave acetate as the active agent, instead of dexamethasone. Theimplant or implants can be loaded with a total of about 15 mg of theanecortave (i.e. 5 mg of anecortave can be loaded into each of the threeimplants prepared according to the Example 1 method.

The anecortave acetate extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect. The ocularcondition can be an angiogenic condition or an inflammatory conditionsuch as uveitis or the patient can be afflicted with one or more of thefollowing afflictions: macular degeneration (including non-exudative agerelated macular degeneration and exudative age related maculardegeneration); choroidal neovascularization; acute macularneuroretinopathy; macular edema (including cystoid macular edema anddiabetic macular edema); Behcet's disease, diabetic retinopathy(including proliferative diabetic retinopathy); retinal arterialocclusive disease; central retinal vein occlusion; uveitic retinaldisease; retinal detachment; retinopathy; an epiretinal membranedisorder; branch retinal vein occlusion; anterior ischemic opticneuropathy; non-retinopathy diabetic retinal dysfunction, retinitispigmentosa and glaucoma. The implant(s) can be inserted into thevitreous using known procedures (trocar implantation). The implant(s)can release a therapeutic amount of the anecortave for an extendedperiod of time to thereby treat a symptom of the ocular condition.

Example 4 Preparation and Therapeutic Use of an Anti-VEGF ExtendedRelease Implant(s)

VEGF (Vascular Endothelial Growth Factor) (also known as VEGF-A) is agrowth factor, which can stimulate vascular endothelial cell growth,survival, and proliferation. VEGF is believed to play a central role inthe development of new blood vessels (angiogenesis) and the survival ofimmature blood vessels (vascular maintenance). Tumor expression of VEGFcan lead to the development and maintenance of a vascular network, whichpromotes tumor growth and metastasis. Thus, increased VEGF expressioncorrelates with poor prognosis in many tumor types. Inhibition of VEGFcan be an anticancer therapy used alone or to complement currenttherapeutic modalities (e.g., radiation, chemotherapy, targeted biologictherapies).

VEGF is believed to exert its effects by binding to and activating twostructurally related membrane receptor tyrosine kinases, VEGF receptor-1(VEGFR-1 or flt-1) and VEGFR-2 (flk-1 or KDR), which are expressed byendothelial cells within the blood vessel wall. VEGF may also interactwith the structurally distinct receptor neuropilin-1. Binding of VEGF tothese receptors initiates a signaling cascade, resulting in effects ongene expression and cell survival, proliferation, and migration. VEGF isa member of a family of structurally related proteins (see Table Abelow). These proteins bind to a family of VEGFRs (VEGF receptors),thereby stimulating various biologic processes. Placental growth factor(PIGF) and VEGF-B bind primarily to VEGFR-1. PIGF modulates angiogenesisand may also play a role in the inflammatory response. VEGF-C and VEGF-Dbind primarily to VEGFR-3 and stimulate lymphangiogenesis rather thanangiogenesis.

TABLE A VEGF Family Members Receptors Functions VEGF (VEGF-A) VEGFR-1,VEGFR-2, Angiogenesis Vascular neuropilin-1 maintenance VEGF-B VEGFR-1Not established VEGF-C VEGF-R, VEGFR-3 Lymphangiogenesis VEGF-D VEGFR-2,VEGFR-3 Lymphangiogenesis VEGF-E (viral VEGFR-2 Angiogenesis factor)PIGF VEGFR-1, neuropilin-1 Angiogenesis and inflammation

An extended release bioerodible implant system can be used to treat anocular condition mediated by a VEGF. Thus, the implant can contain asactive agent a compound with acts to inhibit formation of VEGF or toinhibit the binding of VEGF to its VERFR. The active agent can be, forexample, ranibizumab (rhuFab V2) (Genentech, South San Francisco,Calif.) and the implant(s) can be made using the method of Example 1,but with use of ranibizumab as the active agent, instead ofdexamethasone. Ranibizumab is an anti-VEGF (vascular endothelial growthfactor) product, which may have particular utility for patients withmacular degeneration, including the wet form of age-related maculardegeneration. The implant or implants can be loaded with a total ofabout 300-500 μg of the ranibizumab (i.e. about 150 μg of ranibizumabcan be loaded into each of the three implants prepared according to theExample 1 method.

The ranibizumab extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the ranibizumab for anextended period of time to thereby treat a symptom of the ocularcondition.

Pegaptanib is an aptamer that can selectively bind to and neutralizeVEGF and may have utility for treatment of, for example, age-relatedmacular degeneration and diabetic macular edema by inhibiting abnormalblood vessel growth and by stabilizing or reverse blood vessel leakagein the back of the eye resulting in improved vision. A bioerodibleimplant system for extended delivery of pegaptanib sodium (Macugen;Pfizer Inc, New York or Eyetech Pharmaceuticals, New York) can also bemade using the method of Example 1 or the method of Example 4, but withuse of pegaptanib sodium as the active agent, instead of dexamethasone.The implant or implants can be loaded with a total of about 1 mg to 3 mgof Macugen according to the Example 1 method.

The pegaptanib sodium extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect.

An extended release bioerodible intraocular implant for treating anocular condition, such as an ocular tumor can also be made as set forthin this Example 9, using about 1-3 mg of the VEGF Trap compoundavailable from Regeneron, Tarrytown, N.Y.

Example 5 Preparation and Therapeutic Use of Beta Blocker ExtendedRelease Implant(s)

An extended release implant system to treat an ocular condition cancontain a beta-adrenergic receptor antagonist (i.e. a “beta blocker)such as levobunolol, betaxolol, carteolol, timolol hemihydrate andtimolol. Timolol maleate is commonly used to treat of open-angleglaucoma. Thus, an extended release bioerodible implant systemcontaining timolol maleate (available from multiple different suppliersunder the tradenames Timoptic, Timolol or Loptomit) as the active agentcan be made using the method of Example 1, but with use of timololmaleate instead of dexamethasone. Thus, about 50 μg to 150 μg of thetimolol maleate can be loaded into each of the three implants preparedaccording to the Example 1 method.

The timolol extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the timolol for anextended period of time to thereby treat a symptom of the ocularcondition by, for example, causing an intraocular pressure depression.

Example 6 Preparation and Therapeutic Use of Prostamide Extended ReleaseImplant(s)

An extended release implant system can be used to treat an ocularcondition can contain a prostamide. Prostamides are naturally occurringsubstances biosynthesized from anandamide in a pathway that includesCOX2. Bimatoprost (Lumigan) is a synthetic prostamide analog chemicallyrelated to prostamide F. Lumigan has been approved by the FDA for thereduction of elevated intraocular pressure (IOP) in patients withopen-angle glaucoma or ocular hypertension who are intolerant of orinsufficiently responsive to other IOP-lowering medications. Lumigan isbelieved to lower intraocular pressure by increasing the outflow ofaqueous humor.

Thus, an extended release bioerodible implant system containing Lumigan(Allergan, Irvine, Calif.) as the active agent can be made using themethod of Example 1, but with use of timolol maleate instead ofdexamethasone. Thus, about 100 μg to 300 μg of Lumigan can be loadedinto each of the three implants prepared according to the Example 1method.

The Lumigan extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the Lumigan for anextended period of time to thereby treat a symptom of the ocularcondition by, for example, causing an intraocular pressure depression.

Example 7 Preparation and Therapeutic Use of an Alpha-2 Extended ReleaseImplant(s)

An extended release implant system can be used to treat an ocularcondition wherein the implant contains as the active agent an alpha-2adrenergic receptor agonist, such as clonidine, apraclonidine, orbrimonidine. Thus, an extended release bioerodible implant systemcontaining brimonidine (Allergan, Irvine, Calif., as Alphagan orAlphagan P) as the active agent can be made using the method of Example1, but with use of Alphagan instead of dexamethasone. Thus, about 50 μgto 100 μg of Alphagan can be loaded into each of the three implantsprepared according to the Example 1 method.

The brimonidine extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the brimonidine for anextended period of time to thereby treat a symptom of the ocularcondition by, for example, causing an intraocular pressure depression.

Example 8 Preparation and Therapeutic Use of a Retinoid Extended ReleaseImplant(s)

An extended release implant system can be used to treat an ocularcondition. The implant can contain a retinoid such as an ethylnicotinate, such as a tazarotene. Thus, an extended release bioerodibleimplant system containing tazarotene (Allergan, Irvine, Calif.) as theactive agent can be made using the method of Example 1, but with use oftazarotene instead of dexamethasone. Thus, about 100 μg to 500 μg oftazarotene can be loaded into each of the three implants preparedaccording to the Example 1 method.

The tazarotene extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the tazarotene for anextended period of time to thereby treat a symptom of the ocularcondition by, for example, causing an intraocular pressure depression.

Example 8 Preparation and Therapeutic Use of a Tyrosine Kinase InhibitorExtended Release Implant(s)

Generally, tyrosine kinase inhibitors are small molecule inhibitors ofgrowth factor signaling. Protein tyrosine kinases (PTKs) comprise alarge and diverse class of proteins having enzymatic activity. The PTKsplay an important role in the control of cell growth anddifferentiation. For example, receptor tyrosine kinase mediated signaltransduction is initiated by extracellular interaction with a specificgrowth factor (ligand), followed by receptor dimerization, transientstimulation of the intrinsic protein tyrosine kinase activity andphosphorylation. Binding sites are thereby created for intracellularsignal transduction molecules and lead to the formation of complexeswith a spectrum of cytoplasmic signaling molecules that facilitate theappropriate cellular response (e.g., cell division, metabolichomeostasis, and responses to the extracellular microenvironment).

With respect to receptor tyrosine kinases, it has been shown also thattyrosine phosphorylation sites function as high-affinity binding sitesfor SH2 (src homology) domains of signaling molecules. Severalintracellular substrate proteins that associate with receptor tyrosinekinases (RTKs) have been identified. They may be divided into twoprincipal groups: (1) substrates, which have a catalytic domain; and (2)substrates, which lack such domain but serve as adapters and associatewith catalytically active molecules. The specificity of the interactionsbetween receptors or proteins and SH2 domains of their substrates isdetermined by the amino acid residues immediately surrounding thephosphorylated tyrosine residue. Differences in the binding affinitiesbetween SH2 domains and the amino acid sequences surrounding thephosphotyrosine residues on particular receptors are consistent with theobserved differences in their substrate phosphorylation profiles. Theseobservations suggest that the function of each receptor tyrosine kinaseis determined not only by its pattern of expression and ligandavailability but also by the array of downstream signal transductionpathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step, which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

Aberrant expression or mutations in the PTKs have been shown to lead toeither uncontrolled cell proliferation (e.g. malignant tumor growth) orto defects in key developmental processes. Consequently, the biomedicalcommunity has expended significant resources to discover the specificbiological role of members of the PTK family, their function indifferentiation processes, their involvement in tumorigenesis and inother diseases, the biochemical mechanisms underlying their signaltransduction pathways activated upon ligand stimulation and thedevelopment of novel drugs.

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular). The RTKs comprise a large family of transmembranereceptors with diverse biological activities. The intrinsic function ofRTKs is activated upon ligand binding, which results in phosphorylationof the receptor and multiple cellular substrates, and subsequently in avariety of cellular responses.

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, is believedto be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Hersubfamily of receptors include epithelial growth factor (EGF), TGF-α,amphiregulin, HB-EGF, betacellulin and heregulin.

A second family of RTKs, designated the insulin subfamily, is comprisedof the INS—R, the IGF-1R and the IR—R. A third family, the “PDGF”subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the Kinase insert Domain-Receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosinekinase 1 (flt-1). Each of these receptors was initially believed to bereceptors for hematopoietic growth factors. Two other subfamilies ofRTKs have been designated as the FGF receptor family (FGFR1, FGFR2,FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).

Because of the similarities between the PDGF and FLK subfamilies, thetwo subfamilies are often considered together. The known RTK subfamiliesare identified in Plowman et al, 1994, DN&P 7(6): 334-339, which isincorporated herein by reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes that lack extracellular and transmembrane sequences. At present,over twenty-four individual non-receptor tyrosine kinases, comprisingeleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak,Jak, Ack and LIMK) have been identified. At present, the Src subfamilyof non-receptor tyrosine kinases is comprised of the largest number ofPTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Srcsubfamily of enzymes has been linked to oncogenesis. A more detaileddiscussion of non-receptor tyrosine kinases is provided in Bolen, 1993,Oncogene 8: 2025-2031, which is incorporated herein by reference.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysleading to cellular signal cascades leading to pathogenic conditions,including cancer, psoriasis and hyper immune response.

In view of the surmised importance of PTKs to the control, regulationand modulation of cell proliferation the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify receptor and non-receptor tyrosine kinase “inhibitors”using a variety of approaches, including the use of mutant ligands (U.S.Pat. No. 4,966,849), soluble receptors and antibodies (PCT ApplicationNo. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci 90:10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek,et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al,1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (PCTApplication Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808;U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. CancerRes. 35: 2268).

An extended release implant system can be used to treat an ocularcondition wherein the implant contains a tyrosine kinase inhibitor (TKI)such as a TKI set forth in published U.S. patent application 200400019098 (available from Allergan, Irvine, Calif.) as the active agentcan be made using the method of Example 1, but with use of a TKI insteadof dexamethasone. Thus, about 100 μg to 300 μg of a TKI can be loadedinto each of the three implants prepared according to the Example 1method.

The TKI extended release implant system can be implanted into an ocularregion or site (i.e. into the vitreous) of a patient with an ocularcondition for a desired therapeutic effect. The ocular condition can bean inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known the procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the TKI for an extendedperiod of time to thereby treat a symptom of the ocular condition by,for example, causing an intraocular pressure depression.

Example 9 Preparation and Therapeutic Use of an NMDA Antagonist ExtendedRelease Implant(s)

It is believed that overstimulation of the N-methyl-D-aspartate (NMDA)receptor by glutamate is implicated in a variety of disorders. Memantineis an NMDA antagonist that can be used to reduce neuronal damagemediated by the NMDA receptor complex. Memantine is an available formMerz Pharmaceuticals, Greensboro, N.C. under the tradename Axura. Anextended release implant system can be used to treat an ocularcondition. The implant can contain an NMDA antagonist such as memantine.Thus, an extended release bioerodible implant system containingmemantine as the active agent can be made using the method of Example 1,but with use of memantine instead of dexamethasone. Thus, about 400 μgto 700 μg of memantine can be loaded into each of the three implantsprepared according to the Example 1 method.

The memantine extended release implant system can be implanted into anocular region or site (i.e. into the vitreous) of a patient with anocular condition for a desired therapeutic effect. The ocular conditioncan be an inflammatory condition such as uveitis or the patient can beafflicted with one or more of the following afflictions: maculardegeneration (including non-exudative age related macular degenerationand exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the memantine for anextended period of time to thereby treat a symptom of the ocularcondition.

Example 10 Preparation and Therapeutic Use of an Estratropone ExtendedRelease Implant(s)

Certain estratropones have anti-angiogenesis, anti-neoplastic andrelated useful therapeutic activities. An extended release implantsystem can be used to treat an ocular condition. The implant can containan estratropone such as 2-methoxyestradiol (available form Entremed,Inc., of Rockville, Md. under the tradename Panzem). Thus, an extendedrelease bioerodible implant system containing memantine as the activeagent can be made using the method of Example 1, but with use of2-methoxyestradiol instead of dexamethasone. 2-methoxyestradiol can beused as a small molecule angiogenic inhibitor to block abnormal bloodvessel formation in the back of the eye. Thus, about 400 μg to 700 μg of2-methoxyestradiol can be loaded into each of the three implantsprepared according to the Example 1 method.

The 2-methoxyestradiol extended release implant system can be implantedinto an ocular region or site (i.e. into the vitreous) of a patient withan ocular condition for a desired therapeutic effect. The ocularcondition can be an inflammatory condition such as uveitis or thepatient can be afflicted with one or more of the following afflictions:macular degeneration (including non-exudative age related maculardegeneration and exudative age related macular degeneration); choroidalneovascularization; acute macular neuroretinopathy; macular edema(including cystoid macular edema and diabetic macular edema); Behcet'sdisease, diabetic retinopathy (including proliferative diabeticretinopathy); retinal arterial occlusive disease; central retinal veinocclusion; uveitic retinal disease; retinal detachment; retinopathy; anepiretinal membrane disorder; branch retinal vein occlusion; anteriorischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction,retinitis pigmentosa and glaucoma. The implant(s) can be inserted intothe vitreous using known procedures (trocar implantation). Theimplant(s) can release a therapeutic amount of the 2-methoxyestradiolfor an extended period of time to thereby treat a symptom of the ocularcondition.

Using the same methodology, additional extended release single ormultiple polymer implants can be prepared wherein the active agent is,for example, an agent to treat intravitreal hemorrhage (such as Vitrase,available from Ista Pharmaceuticals), an antibiotic (such ascyclosporine, or gatifloxacin, the former being available from Allergan,Irvine, Calif. under the tradename Restasis and the later from Allerganunder the tradename Zymar), ofloxacin, an androgen, epinastine (Elestat,Allergan, Irvine, Calif.), an anti-coagulant, a metalloproteaseinhibitor, a carbonic anhydrase inhibitor, a GABA receptor agonist, acalcium channel antagonist, or with a combination of two or more activeagents (such as a combination in a single extended release implant of aprostamide (i.e. brimatoprost) and a best blocker (i.e. timolol) or acombination of an alpha 2 adrenergic agonist (i.e. brimonidine) and abeta blocker, such as timolol) in the same extended delivery system. Animplant within the scope of the present invention can be used inconjunction with a photodynamic therapy or laser procedure upon an eyetissue.

All references, articles, patents, applications and publications setforth above are incorporated herein by reference in their entireties.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

1. A method of manufacturing a drug delivery system which comprises asegmented bioerodible implant, the method comprising: a) blending afirst active agent with a first bioerodible polymer to form a firstactive agent polymer mixture; b) forming the first active agent polymermixture into a rod shaped first implant segment having a longitudinalaxis; c) blending a second active agent with a second bioerodiblepolymer to form a second active agent polymer mixture; d) forming thesecond active agent polymer mixture into a rod shaped second implantsegment having a longitudinal axis; e) joining the segments at the endsthereof to permit separation from each other in situ into individualsegments following implantation into a patient; wherein each of thesegments is formed with at least one end having a cut surface that is atan angle to the longitudinal axis of less than 90° or one end having abeveled shaped surface; wherein at least one of the segments is formedby a double extrusion process; and wherein the segments erode atdifferent rates in situ.
 2. The method according to 1, wherein the firstand second bioerodible polymer comprises at least one member selectedfrom the group consisting of poly(lactide) polymers andpoly(lactide-co-glycolide) copolymers.
 3. The method according to claim1, wherein at least one excipient that modifies the erosioncharacteristics of the bioerodible polymer is blended with the activeagent and the bioerodible polymer, and wherein the first and secondactive agent polymer mixtures comprise different excipients.
 4. Themethod according to claim 3, wherein the at least one excipient is amember selected from the group consisting of long chain fatty alcohols,cholesterol, and high molecular weight polyethylene glycol polymers. 5.The method according to claim 1, wherein the first and/or secondbioerodible polymer comprises a poly(D,L-lactide-co-glycolide) copolymerwith a monomer ratio in the range of 50:50 to 85:15.